Ferroportin is an iron efflux pump that plays a key role in maintaining systemic body iron homeostasis. It is regulated by the peptide hormone hepcidin, which is made by the liver and circulates systemically. Ferroportin and hepcidin are central to assuring that iron delivery to the circulation is matched to systemic iron demand: mutations in ferroportin and hepcidin lead to inappropriate dietary iron uptake and retention, and result in hemochromatosis, a disease of iron overload. In the last grant cycle, we discovered that ferroportin and hepcidin are also manufactured in breast tissue, are essential to maintenance of iron homeostasis in the breast, and that disruption of this regulatory axis was a critical component of the transformed phenotype. In this application, we leverage these observations, as well as observations we made in the last grant period on how inflammatory, oncogenic and oxidative stress signals regulate ferreting, ferroportin and iron, to understand how iron trafficking and signaling are handled in the breast. We will explore the mechanistic link between disruptions of these regulatory circuits and their pathophysiological consequences. We will test whether blocking these pathways can modify disease progression in mouse models. We explore the fundamental iron biology that underpins these observations in three specific aims. We will explore (Aim 1) a novel autocrine and paracrine iron regulatory network in breast tissue that we recently uncovered, particularly the relationship and regulation of hepcidin and ferroportin by bone morphogenic proteins (BMPs) and their endogenous inhibitors. We will also study in detail the heretofore unrecognized transcriptional repression of ferroportin (Aim 2). Finally (Aim 3), we will address how classic systemic iron regulation mediated through liver- produced hepcidin interacts with this paracrine iron-regulatory axis in the breast. Taken together, we believe the proposed experiments break new ground by defining heretofore unknown pathways and new target tissues in the regulation of iron homeostasis and their link to disease. PUBLIC HEALTH RELEVANCE: This proposal will allow us to better understand iron regulation in cells and tissues. We will specifically test whether interceding in iron-regulatory pathways can modify disease processes in breast tissue. Understanding these iron- regulatory networks is a critical first step to modifying these pathways for therapeutic benefit in a wide array of conditions, including cancer and inflammatory diseases such as arthritis, as well as the anemia that accompanies inflammation and chronic disease.